Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the fourth major cause of death in the developed world after heart disease, cancer and stroke. AD is strongly influenced by genetics, with current estimates suggesting that greater than 40% of all AD cases are familial (FAD). Genetic investigations have demonstrated that AD is a heterogeneous disorder with several known etiologies including: dosage imbalance for chromosome 21 as occurs in Down syndrome (DS); mutations in the amyloid precursor protein (APP) gene on chromosome 21, the presenilin-1 (PS-1) gene on chromosome 14 and the presenilin-2 (PS-2) gene on chromosome 1 in autosomal dominant early-onset FAD; and inheritance of distinct alpha-2 microglobulin and apolipoprotein E (ApoE) gene alleles on chromosome 12 and 19, respectively, as significant genetic risk factors for late-onset FAD. Additional genetic risk factors for AD are certain to exist. A pathologic hallmark in the brains of individuals with AD is deposits of the beta- amyloid (Abeta) peptide in the parenchyma of amygdala, hippocampus and neocortex. One of the major difficulties in studying the mechanism(s) of Abeta deposition and its impact on AD-related neuropathology, behavior and physiology is the paucity of accurate animal models. To establish an accurate genetic model for AD, we have focused on introducing entire genomic copies of either wild-type (wt) or mutant human APP and PS-1 genes carried on yeast artificial chromosomes (YACs) into the mouse germline and have recently demonstrated that a threshold into the molecular and mechanisms of the disease. The specific aims of the current proposal are to examine the effect of specific human AD genetic risk factors, namely dosage imbalance for genes on chromosome 21 (in the Ts65Dn mouse model of DS) and the various ApoE alleles (in ApoE knock-in mice), across the lifespan of APP YAC transgenic mice on: 1) Localization and timing of Abeta deposition and other structural neuropathology. 2) Learning and memory deficits characteristic of individuals with AD.